bims-prodis 2018-08-05 papers

Issue of 2018–08–05
four papers selected by
Nancy Gough, Bioserendipity

Semin Cancer Biol. 2018 Jul 25. pii: S1044-579X(18)30039-7. [Epub ahead of print]

Challenges and opportunities in the proteomic characterization of clear cell renal cell carcinoma (ccRCC): A critical step towards the personalized care of renal cancers.

Qing Kay Li, Christian P Pavlovich, Hui Zhang, Christopher R Kinsinger, Daniel W Chan.

Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer, comprising approximately 75% of all kidney tumors. Recent the Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) studies have significantly advanced the molecular characterization of RCC and facilitated the development of targeted therapies. Such advances have improved the median survival of patients with advanced disease from less than 10 months prior to 2004 to 30 months by 2011. However, approximately 30% of localized ccRCC patients will nevertheless develop recurrence or metastasis after surgical resection of their tumor. Therefore, it is critical to further analyze potential tumor-associated proteins and their profiles during disease progression. Over the past decade, tremendous effort has been focused on the study of molecular pathways, including genomics, transcriptomics, and proteomics in order to identify potential molecular biomarkers, as well as to facilitate early detection, monitor tumor progression and uncover potentially therapeutic targets. In this review, we focus on recent advances in the proteomic analysis of ccRCC, current strategies and challenges, and perspectives in the field. This insight will highlight the discovery of tumor-associated proteins, and their potential clinical impact on personalized precision-based care in ccRCC.

Keywords: Clear cell renal cell carcinoma (ccRCC); Clinical application; Personalized medicine; Protein profiling; Proteomics

DOI: https://doi.org/10.1016/j.semcancer.2018.06.004

J Proteomics. 2018 Jul 26. pii: S1874-3919(18)30295-1. [Epub ahead of print]

Label-free quantitative proteomics of rat hypothalamus under fever induced by LPS and PGE2.

Marina Firmino, Simone N Weis, Jaques M F Souza, Bruna R B Gomes, Alan R Mól, Márcia R Mortari, Gloria E P Souza, Guilherme C Coca, Thomas C R Williams, Wagner Fontes, Carlos André O Ricart, Marcelo V de Sousa, Fabiane H Veiga-Souza.

Fever is a brain-mediated increase in body temperature mainly during inflammatory or infectious challenges. Although there is considerable data regarding the inflammation pathways involved in fever, metabolic alterations necessary to orchestrate the complex inflammatory response are not totally understood. We performed proteomic analysis of rat hypothalamus using label-free LC-MS/MS in a model of fever induced by lipopolysaccharide (LPS) or prostaglandin E2 (PGE2). In total, 7021 proteins were identified. As far as we know, this is the largest rat hypothalamus proteome dataset available to date. Pathway analysis showed proteins from both stimuli associated with inflammatory and metabolic pathways. Concerning metabolic pathways, rats exposed to LPS or PGE2 presented lower relative abundance of proteins involved in glycolysis, pentose phosphate pathway and tricarboxylic acid cycle. Mitochondrial function may also be altered by both stimuli because significant downregulation of several proteins was found, mainly in complexes I and IV. LPS was able to induce downregulation of important proteins in the enzymatic antioxidant system, thereby contributing to oxidative stress. The results offered comprehensive information about fever responses and helped to reveal new insights into proteins potentially involved in inflammatory signaling and metabolic changes in the hypothalamus during systemic LPS and central PGE2 administration.
SIGNIFICANCE: The evolutionary persistence of fever, despite the elevated cost for maintenance of this response, suggests that elevation in core temperature may represent an interesting strategy for survival. Fever response is achieved through the integrated behavioral, physiological, immunological and biochemical processes that determine the balance between heat generation and elimination. The development of such complex response arouses interest in studying how the cell metabolism responds or even contributes to promote fever. Our results offered comprehensive information about fever responses, including metabolic and inflammatory pathways, providing new insights into candidate proteins potentially involved in inflammatory signaling and metabolic changes in the hypothalamus during fever induced by systemic LPS and central PGE2 perturbation.

Keywords: Fever; Hypothalamus; Lipopolysaccharide; Metabolism; Prostaglandin E(2); Proteome

DOI: https://doi.org/10.1016/j.jprot.2018.07.018

Transl Oncol. 2018 Jul 26. pii: S1936-5233(18)30204-3. [Epub ahead of print]11(5): 1160-1170

Expression Analysis of Platinum Sensitive and Resistant Epithelial Ovarian Cancer Patient Samples Reveals New Candidates for Targeted Therapies.

K Veskimäe, M Scaravilli, W Niininen, H Karvonen, S Jaatinen, M Nykter, T Visakorpi, J Mäenpää, D Ungureanu, S Staff.

Ovarian cancer has the highest mortality rate of all gynecologic malignancies. Identification of new biomarkers is highly needed due to its late diagnosis and high recurrence rate. The objective of this study was to identify mechanisms of therapy resistance and potential biomarkers by analyzing mRNA and protein expression from samples derived from patients with platinum-sensitive and -resistant ovarian cancer (total cohort n = 53). The data revealed new candidates for targeted therapies, such as GREB1 and ROR2. We showed that the development of platinum resistance correlated with upregulation of ROR2, whereas GREB1 was downregulated. Moreover, we demonstrated that high levels of ROR2 in platinum-resistant samples were associated with upregulation of Wnt5a, STAT3 and NF-kB levels, suggesting that a crosstalk between the non-canonical Wnt5a-ROR2 and STAT3/NF-kB signaling pathways. Upregulation of ROR2, Wnt5a, STAT3 and NF-kB was further detected in a platinum-resistant cell-line model. The results of the present study provided insight into molecular mechanisms associated with platinum resistance that could be further investigated to improve treatment strategies in this clinically challenging gynecological cancer.

DOI: https://doi.org/10.1016/j.tranon.2018.07.010

Chem Biol Interact. 2018 Jul 25. pii: S0009-2797(18)30814-7. [Epub ahead of print]293 61-69

Indolyl-chalcone derivatives induce hepatocellular carcinoma cells apoptosis through oxidative stress related mitochondrial pathway in vitro and in vivo.

Xinrui Zhang, Mengya Wang, Shanshan Teng, Di Wang, Xin Li, Xiaofeng Wang, Weiwei Liao, Di Wang.

A facile method of assembling oxindole and phthalide units through a Lewis based catalyzed allylic alkylation reaction of Morita-Baylis-Hillman carbonates of isatins and 3-cyanophthalides was recently developed. The method efficiently delivers a hybrid of 3,3'-disubstituted oxindole with a valuable phthalide pharmacophore. In the present study, we proved the deleterious effects of 5h2c, a screened synthesis compound, against hepatocellular carcinoma (HCC) in both in vitro and in vivo models. 5h2c strongly decreased cell viability, caused over-release of lactate dehydrogenase, inhibited cell migration, and enhanced the apoptosis rate in HepG2 and PLC/PRF/5 cells. 5h2c led to an increase in intracellular reactive oxygen species levels and a decrease in mitochondrial membrane potential. In HepG2-and PLC/PRF/5-xenograft tumor mouse models, treatment with 5h2c inhibited tumor growth without affecting the animals' bodyweight or organ functions. Proteome profiling of tumor tissues after 24-h exposure to 5h2c showed significantly enhanced expression levels of Bcl-2 associated X protein, cleaved caspase -3, -8, and -9, nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), heme oxygenase-2, paraoxonase 2, catalase, and factor associated suicide ligand, and reduced the expression levels of B-cell lymphoma-2, B-cell lymphoma-extra large, heat shock protein 27, heat shock protein 60, and heat shock protein 70 in HepG2 and PLC/PRF/5 cells. All of our data confirmed that oxidative stress-mediated mitochondrial apoptosis (especially the Nrf-2/HO-1 pathway) is responsible for 5h2c-induced HCC damage.

Keywords: Apoptosis; Hepatocellular carcinoma; Indolyl-chalcone derivatives; Mitochondria; Oxidative stress

DOI: https://doi.org/10.1016/j.cbi.2018.07.025